Many clinically successful anticancer drugs are themselves either natural products or have been developed from naturally occurring lead compounds. Great interest is currently being paid to drugs isolated from natural resources which have already been used as a medicine. The dried whole plant of Scutellaria barbata D. Don (Labiatae) is used in Traditional Chinese Medicine as an anti-inflammatory, an antitumour agent, and a diuretic. The α,β-unsaturated ketone, (E)-1-(4′-hydroxyphenyl)but-1-en-3-one has been isolated from this plant and found to have moderate antitumour activity (IC50 of 60 μM for K562).

Various analogues of this compounds have been examined for antitumour activity, including one class of analogs, chalcones.
Chalcone, also known as chalkone, benzylideneacetophenone, benzalacetophenone, and phenyl styryl ketone, is 1,3-diphenyl-2-propen-1-one, and has the following structure:

A number of substituted chalcones have been prepared, with one or more substituents on the styryl phenyl group (left, A), the acyl phenyl group (right, B), and/or the double bond carbon atoms.
A number of substituted chalcones with apparent biological activity have been reported.
Hall et al., 1981, describe a number of substituted chalcones which were alleged to have anti-inflammatory properties. The recited compounds are shown below (see Example 10, therein) (substituent is H unless otherwise specified): 1 (X═OH, Z=OH, L=OH), 2 (X═OH, Y═OH, Z=OH, L=OMe), 3 (Y═OH, L=NMe2), 4 (Y═OH, L=Cl), 5 (Y═OH, K=OEt, L=OH), 6 (Y═OH, K=C6H5F), 7 (Y═OH, L=OH), 8 (Y═OMe, K=OMe), 9 (Y═OH, J=F), and 10 (Y═OMe, L=OH).

Eda Shoei et al., 1986, describe several substituted chalcones which were reported to have anti-allergic activity. Compounds 1 (X═H, Y═H), 2 (X═H, Y═H), 3 (X═OH, Y═H), 4 (X═OMe, Y═H), 5 (X═OMe, Y═OMe), 6 (X═NO2, Y═H), 7 (X═NH2, Y═H), (see Table 1, therein) are shown below.

Berryman et al., 1995, 1997, describe a number of substituted chalcones which are intermediates used in the preparation of certain furanone and thiofuranone compounds reported to have activity as endothelin I antagonists.
Some of the chalcone intermediates have a 3,4-methylenedioxy group on the A-ring, as shown in the core structure below. See, e.g., in Berryman et al., 1995, Examples 36, 155, 187, 191, 195, 200, 201, 205, 209, 213, 217, 224, 232, 238, 242, 246, 263, 268, 280, 287, 288, 289, 298, 326, 345, 352, 353, 354, 355, 357, 366, 367, 368, 369, 370, 371, 378, 380, 387, 405, and 406; and additionally, in Berryman et al., 1997, Examples 421, 435, and 446. Various B-ring substituents are illustrated, including: 4-hydroxy; 2-methoxy; 3-methoxy; 4-methoxy; 2-allyloxy-4-methoxy; 4-isopropoxy; 2,4-dimethoxy; 3,4-dimethoxy; 3,4-methylenedioxy; 3,4-methylenedioxy-5-methoxy; and 3,4-ethylenedioxy.

Although many of the chalcone intermediates have an A-ring substituent which is 4-methoxy, one (Example 1, page 55, in Berryman et al., 1995) has a 4-(C2-6alkoxy) substituent, specifically, a 4-isopropoxy substituent, as shown below.

Ikeda Shunichi et al., 1996, describe several substituted chalcones reported to be active as antitumour agents. Compounds 1 (X═H) (also referred to herein as DMU-103), 2 (X=Me), and 3 (X=Et) (see Table 1, therein) are shown below.

Ducki et al., 1998, describe several substituted chalcones which were screened for cytotoxic activity against the human K562 human leukemia cell line (which does not express CYP1B1). Compounds 2a-d (X═H) and 5a-d (X=Me) (see Table 3, therein) are shown below. The X=Me compounds were found to be much more active against K562 cells than the X═H compounds (see Table 3 therein), thus favouring the presence of the “ene”-substituent. Compound 2b is also referred to herein as DMU-135.

Kharazmi et al., 1999, describe a large number of substituted chalcones alleged to be suitable for the treatment of, inter alia, inflammatory conditions and neoplasias. See, e.g., Example 1 (pages 71-94) therein; the ring numbering scheme, shown below, is illustrated at page 132 therein. None of the compounds have a 4-(C2-6alkoxy) substituent or a 3,4-methylenedioxy substituent (using their numbering scheme).

Potter et al., 1999, 2001a, describe several 3,4,5-trimethoxy chalcones which were shown to inhibit preferentially the growth of cells expressing cytochrome P450 enzyme CYP1B1 as compared to cells which do not. Compounds VI (X═OMe, Y═H, Z=H, cis), VIII (X═OMe, Y═H, Z=H, trans), VIII (X═OH, Y═H, Z=H), IX (X═OMe, Y═OMe, Z=H), XI (X═OMe, Y═H, Z=Me) are shown below. Compound VII was reported to be 200-fold more cytotoxic to the cell line expressing CYP1B1 than to the parental cell line not expressing this enzyme.

Potter et al., 2001 b, describes certain substituted 1-(4-methoxyphenyl)-3-(3,5-dimethoxyphenyl)prop-1-en-3one of the following general formula, which have therapeutic application, and which are potent antiproliferative agents and antiinflammatory agents.

Cushman et al., 1995, describes various stilbene derviatives, which are reported to possess utility as anticancer agents.
There is a great need for additional antiproliferative agents which offer one or more of the following benefits:    (a) improved activity.    (b) improved selectivity (e.g., against tumour cells versus normal cells).    (c) low cytotoxicity as a prodrug, but yields an active drug in vivo;    (d) complement the activity of other treatments (e.g., chemotherapeutic agents);    (e) reduced intensity of undesired side-effects;    (f) fewer undesired side-effects;    (g) simpler methods of administration;    (h) reduction in required dosage amounts;    (i) reduction in required frequency of administration;    (j) increased ease of synthesis, purification, handling, storage, etc.;    (k) reduced cost of synthesis, purification, handling, storage, etc.
Thus, one aim of the present invention is the provision of compounds which are potent antiproliferative agents, e.g., anti-cancer agents, which offer one or more of the above benefits.
The inventors have discovered that certain sub-classes of substituted chalcones, described herein, offer one or more of the above benefits, and additionally are surprisingly and unexpectedly more active than corresponding known analogues.